A case-control study has previously been conducted (1986 - 1991) by the University of Buffalo Department of Social and Preventive Medicine. We are seeking gene-environment and gene-gene interactions. Genotyping for microsomal epoxide hydrolase, alcohol dehydrogenase, glutathione-S-transferase Theta, glutathione-S-transferase M1, CYP1A1, CYP2D6, CYP2E1, APOE, and N-acetyltransferase in post- and premenopausal women has been completed. The p53 mutational spectra will be determined in women with histologically proven cancer. Human sera is being examined for polychlorinated biphenyls. Postmenopausal women with incident, primary breast cancer were found to be at increased risk for smoking if they were NAT2 slow acetylators. This polymorphism governs acetylation of aromatic amines, which are mammary carcinogens in experimental studies. Premenopausal women were not at similar risk, possibly due to differences in the biology of pre- versus postmenopausal breast cancer, or due to a decreased latency and exposure. Separately, light cigarette postmenopausal smokers were at increased risk of breast cancer if they inherited one variant of the CYP1A1 gene. Also, premenopausal smokers with a variant of the CYP2E1 gene were at increased risk. These data suggest that smoking may be an important risk factor for breast cancer in susceptible populations. Studies are currently being conducted to reproduce these findings in another study population, and to provide corroborative evidence using in vitro cultured human breast cells.